Technical Field
The present invention relates to compounds for inhibiting the enzyme eukaryotic elongation factor 2 kinase and use thereof in medical therapies and applications.
Background Art
The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Eukaryotic elongation factor 2 kinase (eEF2K) is an ubiquitous, evolutionally-conserved protein kinase that phosphorylates its only known target, elongation factor 2 (EF2), resulting in arrest of protein translation. (Ryazanov A G, Shestakova E A, Natapov P G. Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation. Nature 1988, 334(6178):170-3; Sivan G, Kedersha N, Elroy-Stein O. Ribosomal slowdown mediates translational arrest during cellular division. Mol. Cel. Biol. 2007, 27(19):6639-46.) EF2 promotes ribosomal translocation, the reaction that results in the movement of the ribosome along mRNA during translation. Phosphorylation of EF2 arrests translation, such that this is a critical mechanism by which the rate of protein synthesis is regulated. (Ryazanov A G. Ca2+/calmodulin-dependent phosphorylation of elongation factor 2. FEBS Lett. 1987, 214:331-3).
Inhibition of eEF2K is of potential utility in treating a number of diseases and conditions, including various types of cancer and radiation injury, and as an adjunct to chemotherapy and similar agents to limit apoptosis of normal cells. Thus one application is as a radioprotective agent, limiting radiation-induced apoptosis with natural radiation, unintentional exposure to radiation and radiation therapy. Another application is to mitigate side effects associated with drug and radiation therapy.
eEF2K inhibitors are known and described in the prior art. (Lockman J W, Reeder M D, Suzuki K, Ostanin K, Hoff R, Bhoite L, et al. Inhibition of eEF2-K by thieno[2,3-b]pyridine analogues. Bioorg. Med. Chem. Lett. 2010, 20(7):2283-6; Chen Z, Gopalakrishnan S M, Bui M-H, Soni N B, Warrior U, Johnson E F, et al. 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2): a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor. J. Biol. Chem. 2011, 286(51):43951-8; and Cho S I, Koketsu M, Ishihara H, Matsushita M, Nairn A C, Fukazawa H, et al. Novel compounds, “1,3-selenazine derivatives” as specific inhibitors of eukaryotic elongation factor-2 kinase. Biochim Biophys Acta 2000, 1475(3):207-15.) However, no eEF2K inhibitor has been developed that is suitable for use as a drug.
There is a significant and substantial need for agents which inhibit eEF2K and which limit or inhibit the phosphorylation of EF2, which agents have properties that are suitable for use as pharmaceutical agents. The present invention addresses this by providing eEF2K inhibitors which may be used as drugs for the treatment or prophylaxis of a variety of diseases and conditions. It is against this background that the present invention as made.